1. Field of the Invention
The present invention relates to formulations for administration by inhalation by means of dry powder inhalers. In particular, the present invention relates to dry powder formulations comprising a combination of an anticholinergic, a beta2-adrenoceptor agonist, and an inhaled corticosteroid, process for their preparation and use thereof for the prevention and/or treatment of respiratory diseases.
2. Discussion of the Background
Respiratory diseases are a common and important cause of illness and death around the world. In fact, many people are affected by inflammatory and/or obstructive lung diseases, a category characterized by inflamed and easily collapsible airways, obstruction to airflow, problems exhaling and frequent medical clinic visits and hospitalizations. Types of inflammatory and/or obstructive lung disease include asthma, bronchiectasis, bronchitis and chronic obstructive pulmonary disease (COPD).
In particular, chronic obstructive pulmonary disease (COPD) is a multi-component disease characterized by airflow limitation and airway inflammation. Exacerbations of COPD have a considerable impact on the quality of life, daily activities and general well-being of patients and are a great burden on the health system. Thus, the aims of COPD management include not only relieving symptoms and preventing disease progression but also preventing and treating exacerbations.
While available therapies improve clinical symptoms and decrease airway inflammation, they do not unequivocally slow long-term progression or address all disease components. With the burden of COPD continuing to increase, research into new and improved treatment strategies to optimize pharmacotherapy is ongoing, and in particular, combination therapies, with a view to their complementary modes of action enabling multiple components of the disease to be addressed. Evidence from recent clinical trials indicates that triple therapy, combining an anticholinergic with an inhaled corticosteroid, and a long-acting β2-adrenoceptor agonist, may provide clinical benefits additional to those associated with each treatment alone in patients with more severe COPD.
Currently, there are several recommended classes of therapy for COPD, of which bronchodilators such as β2-agonists and anticholinergics are the mainstay of symptom management in mild and moderate disease, prescribed on an as-needed basis for mild COPD and as a maintenance therapy for moderate COPD.
Said bronchodilators are efficiently administered by inhalation, thus increasing the therapeutic index and reducing side effects of the active material.
For the treatment of more severe COPD, guidelines recommend the addition of inhaled corticosteroids (ICSs) to long-acting bronchodilator therapy. Combinations of therapies have been investigated with a view to their complementary modes of action enabling multiple components of the disease to be addressed. Data from recent clinical trials indicate that triple therapy, combining an anticholinergic with an ICS and a long-acting β2-agonist (LABA), may provide clinical benefits additional to those associated with each treatment alone in patients with moderate to severe COPD.
An interesting triple combination, presently under investigation, includes:                i) formoterol, particularly its fumarate salt (hereinafter indicated as FF), a long acting beta-2 adrenergic receptor agonist, currently used clinically in the treatment of bronchial asthma, COPD and related disorders;        ii) glycopyrronium bromide, an anticholinergic recently approved for the maintenance treatment of COPD;        iii) beclometasone dipropionate (BDP) a potent anti-inflammatory corticosteroid steroid, available under a wide number of brands for the prophylaxis and/or treatment of asthma and other respiratory disorders.        
Formulations for pressurized metered dose inhalers (pMDIs) containing all said three active ingredients in combination are disclosed in WO 2011/076841 and WO 2011/076843, which are incorporated herein by reference in their entireties.
However, despite their popularity, pMDI formulations may have some disadvantages in particular in elderly patients, mostly due to their difficulty to synchronize actuation from the device with inspiration.
Dry powder inhalers (DPIs) are a valid alternative to MDIs for the administration of drugs to airways and lung. Active ingredients intended for inhalation as dry powders should be used in the form of micronized particles.
In order to manufacture a single suitable DPI product containing said kinds of active ingredients, the dry powder formulation should have acceptable flowability to facilitate both handling and the aerosol performance of all three actives from the device.
This is challenging task, as it is well known that by increasing the numbers and the concentration of the active ingredients, the higher is the risk of forming uneven agglomerates which are detrimental to the possibility of achieving a good uniformity of distribution of the active ingredient in the powder mixture and hence a good accuracy of the dose. Said phenomenon has also a detrimental effect on the flowability of the relevant formulation, which in turn would impact on the capability of the device of delivering the correct dose due to the active particles being unable to leave the inhaler and remaining adhered to its interior.
Therefore, the presence of three active ingredients with different physical and chemical properties to be delivered at three different dosage strengths within the same device creates serious problems in the preparation of homogenous blends as well as in the delivery of them with suitable respirable fractions.
WO 01/78693, which is incorporated herein by reference in its entirety, discloses a technology platform for preparing a dry powder formulation comprising as a carrier, a combination of a fraction of coarse excipient particles and a fine fraction made of fine excipient particles and magnesium stearate.
The formulation therein disclosed is described as freely flowable, physically and chemically stable and capable of delivering both accurate doses and a high fraction of fine active particles (respirable fraction).
However, there are no examples reported demonstrating that said platform would be suitable for a combination of three different active ingredients.
Furthermore, good results in terms of respirable fraction are only obtained if the fine fraction of the carrier is prepared starting from coarse excipient particles and the additive, and subjecting them to co-milling for long times, at least two hours, or to jet-milling.
Therefore it would be highly advantageous to provide a powder formulation for administration with DPIs comprising a combination of an anticholinergic, an inhaled corticosteroid, and a long-acting β2-agonist as active ingredients, overcoming all the aforementioned disadvantages.